2185-LB: Antibody-siRNA Conjugate Targeting Myostatin Preserves Muscle Mass during GLP-1R Agonism

Introduction and Objective: Glucagon-like peptide-1 receptor (GLP-1R) agonists induce lean mass loss concomitant with weight reduction in obese individuals. Current muscle-preserving biologics target the myostatin-activin receptor pathway systemically and exhibit off-target adverse events. Herein, we present a muscle-specific therapeutic strategy utilizing antibody-small interfering RNA (siRNA) conjugates. Methods: Transferrin receptor 1 (TfR1) antibodies were site-specifically conjugated with siRNAs targeting either myostatin (MSTN) or activin receptor type-2B (ActRIIB). Muscle-specific effects were initially evaluated in CD-1 lean mice through leg area measurements and terminal muscle mass quantification. The lead conjugate was subsequently administered to diet-induced obese (DIO) mice co-treated with semaglutide to assess muscle preservation efficacy. Finally, safety profiling and pharmacodynamic evaluation were conducted in cynomolgus monkeys. Results: In CD-1 mice, single administration of the conjugate induced dose-dependent muscle mass augmentation lasting >5 weeks, with MSTN-targeting conjugates demonstrating superior efficacy to ActRIIB-targeting counterparts (Δleg area: +14.8% vs +8.6%). DIO mice receiving semaglutide plus MSTN conjugate exhibited comparable fat mass reduction but 11% greater lean mass retention versus semaglutide monotherapy. Terminal analysis revealed 10-18% weight increases in major skeletal muscles, accompanied by 90% greater MSTN mRNA suppression. Cynomolgus monkey studies confirmed favorable safety profiles and positive change of pharmacodynamic biomarkers. Muscle siRNA retention was at nanomolar levels for more than 12 weeks. Conclusion: Antibody-siRNA conjugate platform enables muscle-specific modulation of myostatin signaling, effectively counteracting GLP-1R agonist-induced lean mass loss while maintaining metabolic efficacy. The prolonged pharmacodynamic profile supports quarterly dosing regimens in clinical translation. Disclosure Y. Xing: Employee; ChainGen Bio. Y. Wu: Employee; ChainGen Bio. X. Zhang: Employee; ChainGen Bio. H. Wu: Employee; ChainGen Bio.